Prophylaxis and treatment of cardiac 3,4,5-trialkoxyphenylalkanoic acids and salts thereof

ABSTRACT

(3,4,5-trialkoxy phenyl) alkanoic acids and their pharmaceutically-acceptable salts for prophylaxis and treatment of cardiac disorders.

United States Patent [1 1 Aldo [ Jan. 29, 1974 PROPI-IYLAXIS AND TREATMENT OF CARDIAC 3,4,5-TRIALKOXYPHENYLALKANOIC ACIDS AND SALTS THEREOF [75] Inventor: Garzia Aldo, Lodi, Italy [73] Assignee: Istituto Chemioterapico Italiano S.p.A., Milan, Italy [22] Filed: June 26, 1970 [21] Appl. No.: 50,327

[52] US. Cl 260/521 R, 260/473 R, 424/317 [51] Int. Cl. C07c 65/02 [58] Field of Search 260/521 R, 512 R Haworth et al., Chem. Abst., 43 3403b.

Koo, J. Am. Chem. Soc., 75 720 (1953).

Gardner et a1., Chem. Abst. 49 950i (1955).

Merck Index, Merck & Co. Inc. (1960), pages 277-278.

Primary ExaminerLorraine A. Weinberger Assistant Examiner-John F. Terapane Attorney, Agent, or Firm-Morton, Bernard, Brown, Roberts & Sutherland; John W. Behringer; Eugene L. Bernard [57] ABSTRACT (3,4,5-tria1koxy phenyl) alkanoic acids and their pharmaceutically-acceptable salts for prophylaxis and treatment of cardiac disorders.

6 Claims, No Drawings 1 PROPHYLAXIS AND TREATMENT OF CARDIAC 3,4,S-TRIALKOXYPHENYLALKANOIC ACIDS AND SALTS THEREOF BACKGROUND OF THE INVENTION This invention relates to a method of prophylaxis and treatment of cardiac disorders. In a particular aspect, it relates to a method of treating ischemic cardiopathy prior to or following a cardiac infarction, disorders of rhythm, and disorders of stimulus transmission by the administration of an alkanoic acid derivative.

The prevention and treatment of cardiac disorders, such as ischemia, thrombosis, cardiac infarction and disorders of rhythm and stimulus transmission, is a serious problem. Many studies have been conducted in an effort to ascertain the underlying causes and to develop a suitable method of preventing or treating these serious problems, particularly cardiac insufficiency and cardiac infarction. The pharmacological methods which have been proposed for preventing cardiac infarction include lowering of bloodcholesterol levels, relaxation of the arteries and administration of anticoagulants. Ventricular fibrillation is a highly dangerous condition which is treated by electric shock administered to the heart muscle, and other rhythm and transmission disorders respond to installation of the pacemaker device.

While the use of these methods has greatly improved the prognosis of cardiac patients, the problem of cardiac disorders generally still remains a severe one and in particular the problems caused by infarction are still grave.

SUMMARY OF THE INVENTION It is an object of this invention to provide a method of prophylaxis and treatment of cardiac disorders.

It is another object of this invention to provide novel pharmacetical compositions suitable for the prophylaxis and treatment of cardiac disorders.

Another object of this invention is to provide a method of prophylaxis and prevention of ischemic cardiopathy, cardiac infarction and disorders of rhythm and stimulus transmission by the administration of derivatives of alkanoic acids.

Other objects of this invention will be readily apparent to those skilled in the art from the disclosure herein.

It has been discovered that administration of compounds corresponding to the following formula CDJ/(A) ceptable salts of the compounds of this invention are preferred.

DETAILED DISCUSSION The compounds of the present invention are prepared generally by the method described in an article appearing in The Journal of the American Chemical Society, Volume LXXV, January-March I 3, by John Koo, at pages 720723.

The article specifically describes the preparation of 'y-(3,4,5-trimethoxybenzoyl)-butyric acid by the reaction at ethyl 3,4,5-trimethoxybenzoylacetate with methyl B-bromopropionate in the presence of sodium in absolute ethanol at low temperature, i.e., 0 C, fol lowed by hydrolysis of the crude ester with sulfuric acid. The 'y-(3,4,5-trimethyoxybenzoyl)-butyric acid is then hydrogenated to produce 8-(3,4,5-trimethoxyphenyl)-valeric acid.

According to the method of the present invention, compounds corresponding to the formula given hereinbefore are administered for the treatment of cardiac ischemia, either prior to or following a cardiac infarction, disorders of the rhythm whether related to the infarction or not, and disorders of stimulus transmission. Administration of these compounds is an effective prophylaxis in cases of an impending cardiac infarction and an effective treatment after infarction has occurred. According to one embodiment of the present invention, the method is employed in veterinary medicine, principally in the treatment of household pets, especially dogs, where cardiac problems are frequently encountered.

Cardiac infarction frequently occurs without prior symptoms or before the patient has sought treatment for the relief of symptoms. However, physicians are frequently able to detect symptoms of an approaching crisis and the administration of the compounds of this invention can be started promptly to obtain prophylactic effects.

The products of the present invention are of a low order of toxicity and no side effects are observed in clinical trials. Pharmacological studies indicate that the principal effect of the compounds of the invention is on the heart. The only observed effect on the circulatory system is an increase in the static blood pressure with no significant change in mean arterial pressure.

The dosage in which the compounds of the present invention can be given vary widely within rather broad limits. Good results have been obtained with as little as 25 mg/kg/day and as much as 500 mg/kg/day. In human clinical cases, all of the disorders cited above generally respond to a dosage of 2-8 grams per day per person, preferably about 6 grams per day. This dosage is intended for an average 60-70 kg individual equivalent to a dosage generally within the range of about 25-200 mg/kg/day. A dosage in the range of about 40-100 mg/kg/day is preferred. The treatment can consist of a single daily dose, or the above dosages can be given fractionally at periodic intervals. A single daily dose is generally preferred for a treatment of cardiac infarction and associated disorders but for prophylaxis, smaller periodic doses, e.g., a 500 mg dose, 6 times daily, is preferred.

Administration of the compounds of this invention can be oral, subcutaneous, intravenous or intraperitoneal. When the compounds of the present invention are by subcutaneous, intraperitoneal or intravenous injection, they are administered as their water-soluble neutral salts. Any soluble, pharmaceutically-acceptable salt is suitable and the sodium and potassium salts are preferred. The sodium salt is particularly preferred. For oral administration the compounds are preferably administered as the free acids but they can also be pharmaceutically-acceptable salts, e.g., as the ammonium, sodium, potassium, magnesium or calcium salt. According to one suitable method, the free acids can be administered mixed with a molar equivalent of sodium or potassium bicarbonate. In the examples, the compounds were administered intraperitoneally as the sodium salt because of its ease of handling as an aqueous solution, but the weights given are for the free acid. When administered orally, the compounds are conveniently administered as tablets containing 500 mg with a suitable binder, many of which are known.

Suitable tablets for human or animal use can conveniently be prepared containing 50-500 mg of the compounds of the present invention, either as the free acid or as a pharmaceutically acceptable salt thereof. Tablets containing as little as 50 mg are suitable for oral administration, especially for infants and small children, and in veterinary medicine, for small animals. Tablets containing less than 50 mg can be prepared, and in special cases may be useful, but generally a dose smaller than 50 mg is too small to be practical because in the average patient the number of tablets required per day would be excessively high for convenience. Tablets containing more than 500 mg can also be prepared, but large tablets are difficult for most patients to swallow.

EXAMPLE 1 In the following example, the experimental procedure descirbed at page 722 of the article in the Journal of The American Chemical Society, Volume LXXV, January-March 1953, was duplicated.

To a solution of 3.5 g. of sodium in 250 ml. of absolute ethanol was added, at 40, 28.2 g. of ethyl 3,4,5- trimethoxybenzoylacetate. The mixture was stirred for 10 minutes, then maintained below during the dropwise addition with continued stirring of 2.17 g. of methyl B-bromopropionate. An interval of an hour was allowed to elapse between the addition of the first 0. l 7- g. portion of the bromo ester and of the remainder. The suspension was stirred for an additional 3 to 4 hours at 5l0, allowed to stand at overnight, diluted with ice-water and acidified with dilute hydrochloric acid. Extraction with ether followed by washing, drying and evaporating yielded 40 g. of a pale yellow oil, which was too unstable for purification.

The crude ester was refluxed with 250 ml. of 20 percent sulfuric acid for 45 hours. The mixture was chilled and the partly gummy crude acid treated with 200 ml. of 5 percent sodium hydroxide. Neutral material was removed by filtration and the filtrate acidified to yield 23 g. (8 lpercent) of almost colorless crystalline material. Recrystallization from water gave colorless plates, m.p. ll8-l20.

A solution of 30 g. of the y -(3,4,5-trimethoxybenzoyl)-butyric acid so obtained in 160 ml. of acetic acid was hydrogenated at 60 and 2040 lb. pressure with 12 g. of 5 percent palladium-carbon catalyst during 4 hours. The catalyst was removed and the filtrate concentrated to 100 ml., then stirred and diluted with 300 ml. of ice-water. The crystalline solid was collected after 2 hours. The yield of colorless material, m.p. 66-68 was 25 g. (percent).

The product is 8(3,4,5-trimethoxyphenyl)-valeric acid having the structure CHaO CHaO

EXAMPLEQ The effect of the compound prepared according to the procedure of Example 1 on the heart is determined in rats by intravenous injection of 1 unit per kilogram of vasopressin (Pitressin, marketed by Parke, Davis Co.), an antidiuretic pituitary hormone. As is known, the administration of vasopressin results in variations of the voltage and the morphology, or shape, of the T- wave. It also causes arrhythmia and produces ischemia of the myocardium. It is determined that these electrocardiographic alterations normally produced by the administration of Pitressin are prevented by the administration of the compound of Example 1.

EXAMPLE 3 EXAMPLE 4 'y-(3,4,STriethoxyphenyl-a-isopropyl butyric acid is prepared in accordance with the procedure of Example 1 except that ethyl 3,4,5-triethoxybenzoylacetate and methyl-a-bromo isovalerate are employed.

EXAMPLE 5 e-(3,4,5 -tripropoxyphenyl)-a-dimethyl caproic acid is prepared in accordance with the procedure of Example 1 except that ethyl 3,4,5-tripropoxybenzoylacetate and methyl-a-dimethyl-y-bromobutyrate are employed.

EXAMPLE 6 'y -(3,5-dimethoxy-4-ethoxyphenyl)-a-isopentyl butyric acid is prepared in accordance with the procedure of Example 1 except that ethyl 3,5-dimethoxy-4- ethoxybenzoyl acetate and methyl-a-bromo isoenanthate are employed.

EXAMPLE 7 3 ,4,5-trimethoxyphenyl -a-isopropyl enanthic acid is prepared in accordance with the procedure of Example valerate is employed.

EXAMPLE 8 A pharmaceutical composition in tablet form was prepared by mixing 500 mg of the compound of Exam- 1 except that methyl-S-bromo-a-isopropyl' ple l with 50 mg of corn starch and 50 mg of sucrose. This mixture was compressed in a tableting machine to make a durable tablet. It is suitable for oral administration to humans or other animals suffering from cardiac disorders. It is particularly suitable for prophylaxis of a suspected impending coronary occlusion resulting in an infarction.

The above examples are representative. For example, the 3,4,5-trialkoxy benzoic acids are well known to the art. See, for example, U. S. Pat. Nos. 3,234,276; 3,364,249 and 3,485,865.

Caproic acid is available in commercial quantity and the commercial grade materials are suitable for preparing the products of this invention. The corresponding valeric, butyric, heptanoic, octanoic and nonanoic acids together with their isomers are prepared by known methods.

The recommended dosage during the first 24 hours following infarction as follows:

2-4 grams by phleboclysis; 1-2 ampoules (each ampoule containing 2,000 mg of the sodium salt of the compound of Example 1 dissolved in sufficient sterilized distilled water to make cc) dissolved in 400-600 cc of saline solution.

2-4 grams by intravenous administration; two-four ampoules divided into two -four administrations (each ampoule containing 1,000 mg of the sodium salt of the compound of Example 1 dissolved in sufficient sterilized distilled water to make 10 cc).

2 grams by intramuscular administration; eight ampoules divided into four administrations (each ampoule containing 250 mg of the sodium salt of the compound of Example 1 and sufficient sterilized distilled water to make 3 cc).

4-6 grams by oral administration; 8-12 tablets (each tablet containing 500 mg of the sodium salt of the compound of Example 1 and sufficient excipient to make one tablet).

4-6 grams by oral administration; 8-12 ampoules (each ampoule containing 1 or 2 grams of the so- I claim: 1. A compound represented by the formula wherein each of R R and R is methyl, ethyl or propyl and A is a saturated aliphatic hydrocarbon radical containing 5-9 carbon atoms substituted with one carboxylic acid group, and pharmaceutically-acceptable salts thereof.

2. A compound represented by the formula wherein each of R R and R is methyl, ethyl or propyl, provided that at least one of R R and R is other than methyl, and pharmaceutically-acceptable salts thereof.

3. The compound of claim 1, wherein R R and R are ethyl and A is a-isopropyl butyric acid.

4. The compound of claim 1, wherein R R and R are propyl and A is a-dimethyl caproic acid.

5. The compound of claim 1, wherein R and R are methyl, R is ethyl and A is a-isopentyl butyric acid.

6. The compound of claim 1 wherein R R and R are methyl and A is a-isopropyl enanthic acid. 

2. A compound represented by the formula
 3. The compound of claim 1, wherein R1, R2 and R3 are ethyl and A is Alpha -isopropyl butyric acid.
 4. The compound of claim 1, wherein R1, R2 and R3 are propyl and A is Alpha -dimethyl caproic acid.
 5. The compound of claim 1, wherein R1 and R3 are methyl, R2 is ethyl and A is Alpha -isopentyl butyric acid.
 6. The compound of claim 1 wherein R1, R2 and R3are methyl and A is Alpha -isopropyl enanthic acid. 